A significant number of patients in intensive care units die from a secondary complication known commonly as “sepsis” or “septic shock”. Medical illness, trauma, complication of surgery, and any human disease state, if sufficiently injurious to the patient, may develop into systemic inflammatory response syndrome (“SIRS”), multi-organ system dysfunction syndrome (“MODS”), and multi-organ system failure (“MOSF”).
The mechanism of SIRS is the excessive release of host derived inflammatory mediators, herein referred to as toxic mediators (“TM”). TM include various cytokines (tumor necrosis factor, TNF; the interleukins; interferon), various prostaglandins (PG I.sub.2, E.sub.2, Leukotrienes), various clotting factors (platelet activating factor, PAF), various peptidases, reactive oxygen metabolites, and various poorly understood peptides which cause organ dysfunction (myocardial depressant factor, MDF). If the inflammatory response is excessive, then injury or destruction to vital organ tissue may result in multiorgan dysfunction syndrome (“MODS”). Sepsis is the single most common cause of SIRS leading to MOSF.
Hemofiltration (“HF”) was developed as a technique to control overhydration and acute renal failure in unstable patients and may use a hemofilter consisting of a cellulose derivatives or synthetic membrane (e.g., polysulfone, polyamide, etc.) fabricated as either a parallel plate or hollow fibre filtering surface. Current HF membranes, when used to treat acute renal failure associated with MOSF have been associated with incidental improvements in organ function other than the kidneys. However, these membranes remain deficient in the treatment of MOSF because their specific design characteristics prevent them from removing TM in the upper molecular weight range of recognized TM.
The pores of most conventional hemofiltration membranes allow passage of molecules up to 30,000 Daltons in water with very few membranes allowing passage of molecules up to 50,000 Daltons. The membranes used to treat renal failure were generally designed to achieve the following specific goals: (i) to permit high conductance of the aqueous phase of blood plasma water needed to permit the formation of ultrafiltrate at a fairly low transmembrane pressure (typically 20-40 mm Hg), which requires a relatively large pore size that incidentally passes molecules of up to 30,000 to 50,000 Daltons; and (ii) to avoid passage of albumin (e.g., 68,000 Daltons). Loss of albumin, and subsequently, oncotic pressure, could cause or aggravate tissue oedema and organ dysfunction (e.g., pulmonary oedema), so hemofilters are often designed to avoid this by having molecular weight exclusion limits well below the molecular weight of albumin (e.g., 68,000 Daltons).
During filtration of protein containing solutions, after only 20 min the accumulation of protein as a gel or polarization layer occurs on the membrane surface. This gel layer dramatically reduces effective pore size, reducing the filterable molecular weights by roughly 10-40%. Therefore, pore sizes selected are somewhat larger than needed, anticipating a reduction in effective size.
U.S. Pat. No. 5,571,418 discloses a novel method of continuous arteriovenous hemofiltration (CAVH) using a polysulfone or similar material, hollow fibre hemofilter with a molecular weight exclusion limit of up to 100,000 to 150,000 Daltons as therapeutic regimen for sepsis, multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS) or other mediator-related diseases.
The device and process described in U.S. Pat. No. 5,571,418 generally contemplates the use of large pore hemofiltration membranes with pore sizes to provide molecular weight exclusion limits of 100,000 to 150,000 Daltons in water. With these higher molecular weight cut-offs, these membranes are designed to remove a wider range of different IM's.
EP-A-0 305 787 discloses permselective asymmetric membranes suitable for hemodialysis and a process for the manufacturing thereof. Said membrane has a special three-layer structure having high diffusive permeability, comprising a first inner layer in the form of a dense rather thin skin, having a thickness below 1 μm and a maximum pore size of about 8 nm, responsible for the sieving properties, a second layer in the form of a sponge structure, having a thickness of about 1 to 15 μm and serving as a support for said first layer and a third layer in the form of a finger structure, giving the membrane a mechanical stability and having a thickness of about 20 to 60 μm. The membrane is manufactured by presolving the hydrophobic first polymer in a solvent, presolving the hydrophilic second polymer in a solvent of preferably the same kind, mixing the two solutions, extruding the mixture through the outer ring slit of a nozzle with two concentric openings, a precipitating liquid including a part of the hydrophilic second polymer flowing through the inner openings, to obtain a coagulated membrane, which is subsequently washed and preferably dried.